1,2,3,4-tetrahydroisoquinolines are chemicals that provide a high level of chemical variability. This chemical property provides an opportunity to make different chemicals that are engineered with desired properties that are used by different industries. 1,2,3,4-tetrahydroisoquinolines are important chemicals that have been used by the pharmaceutical and chemical industry for many years. They have many properties that make them desirable targets of development by the pharmaceutical industry because of their medicinal uses and they continue to be manufactured by the chemical industry on larger scales. They have been used for the treatment of neurological diseases such as depression, schizophrenia and Parkinson's, and are used as neuromuscular anesthetics, antivirals, antimicrobials, antiparasitics and disinfectants. For example, the methyl containing 1,2,3,4-tetrahydroisoquinolines have been investigated for the treatment of Parkinson's disease. In addition, they have been researched for use as calcium agonists to treat other diseases. The high bioavailability, metabolic clearance, and general safety of use of 1,2,3,4-tetrahydroisoquinolines makes them very good medicaments that can be used for the treatment of many diseases. The large chemical variability that exists with 1,2,3,4-tetrahydroisoquinolines allows this class of chemicals to have different medicinal properties.
In addition to the medicinal properties of 1,2,3,4-tetrahydroisoquinolines, several other industries use these chemicals as industrial surfactants, disinfectants, detergents and corrosion inhibitors. These chemicals are also used as additives for oil and gas applications because of the different chemical properties that 1,2,3,4-tetrahydroisoquinolines provide. In addition, these chemicals have been used as pesticides, herbicides and wood preservatives because of the rapid acting and the biodegradable properties that these chemicals have. These desirable chemical properties provide added benefits because the chemicals are not long lasting providing lower environmental impact than other industrial chemicals or additives. Further, 1,2,3,4-tetrahydroisoquinolines are safer to use and handle by personnel providing advantages in safety.
The synthesis of 1,2,3,4-tetrahydroisoquinolines can be accomplished using batch or micro flow scales. Typical batch and flow methods include using the Pictet-Spangler reaction to make isoquinolines from aromatics. However, chemical yields generally tend to be lower without the aid of a flow reactor due to lower process efficiency and increased waste production. Another method includes the Bischler-Napierski reaction which often uses phosphorous containing chemicals that are dangerous and are difficult to use because of safety concerns and are problematic to store for prolonged periods of time. In addition, such methods have multiple steps and do not provide high diastereoselectivities in the final products that are formed. In addition, the starting materials are very expensive and can be difficult to obtain worldwide. These disadvantages can lead to chemical processes that are not efficient and can be very expensive. Therefore, it is beneficial and advantageous to have a process that can make 1,2,3,4-tetrahydroisoquinolines having a high diastereoselectivity and chemical variability in an efficient way. Such a process would provide new 1,2,3,4-tetrahydroisoquinolines with different properties that can be used by many industries.
The 1,2,3,4-tetrahydroisoquinolines that are made using the process of the present invention are made using substituted methyl and phenyl indene chemicals. These indene chemicals are petroleum derived chemicals that are found in crude oil, heavy oil and in other biomass. In addition, they are naturally occurring C9 chemicals that are found in varying quantities in bitumen and coal. Indenes are available in large quantities and can be purchased from chemical corporations worldwide in multi ton amounts. Several indene blends are commercially available that contain different isomers of indene including the methyl and phenyl substituted indenes. This availability from natural sources provides a very inexpensive chemical that is used for the process of the present invention. For example, they can be combined with additives to make a blended high energy fuel that is used by the marine industry. In addition, indenes are used as a chemical component by the plastics industry to make different polymeric products. The indene starting materials that are used in the process of the present invention are very inexpensive providing an economically feasible chemical to be used to make other high value chemicals like 1,2,3,4-tetrahydroisoquinoline that have uses for many industries. The process of the present invention overcomes many problems with current processes that have low chemical yields of final products, unwanted waste products, starting chemical availability, process operational costs, additional safety requirements, and reduced economic feasibility.
In addition, the process of the present invention uses a metal salt blend containing osmium to make 1,2,3,4-tetrahydroisoquinolines. The use of osmium has many advantages because different chemical and pharmaceutical products can be made with high chemical selectivity. Osmium has been used to make diols, carbonyl products and other high value products that are important chemicals used by the chemical and pharmaceutical industry. This solid metal chemical is easily available for large scale applications and in smaller scale applications. Further, osmium can be used as a catalyst to provide lower chemical process costs. These advantages allow osmium to be a versatile and beneficial chemical to use for a chemical process.
Further, the process of the present invention involves the use of a micro flow reactor to make 1,2,3,4-tetrahydroisoquinolines. Flow reactors have been used to make chemicals but have not been disclosed in the art to make highly substituted 1,2,3,4-tetrahydroisoquinolines from indenes leading to more structurally complex molecules. Flow reactors and microreactors can be purchased from different suppliers and provide many advantages in chemical synthesis. Safety concerns are minimized because smaller amounts of chemicals are used, more precise control of temperature and chemical concentrations is achieved and finer control of reaction rates is obtained. The smaller quantities of chemicals that are used minimize explosion and other hazards involved with large scale batch chemistry. Further, the modular design minimizes human exposure to toxic chemicals when making chemical products. In addition, the very precise control of chemical selectivity, concentration, and temperature become very easy to control providing a way to optimize and manufacture chemicals in a shorter period of time providing economic benefits. Further, micro reactors and flow reactors can be numbered up to provide multi ton chemical production. Multi ton quantities of high value chemicals have been made using micro reactors and flow reactors.
Finally, the high level of control that micro reactors and flow reactors can achieve, provide advantages in chemical synthesis when expensive chemicals are used. Currently, micro flow reactors that use osmium to make 1,2,3,4-tetrahydroisoquinolines do not exist. Osmium is expensive and the ability to efficiently use osmium while minimizing waste can provide many advantages from lower operational costs and safety. The development of a micro flow reactor that uses osmium to make 1,2,3,4-tetrahydroisoquinolines can be beneficial for several industries including the chemical, pharmaceutical, and petroleum industries because of the increase in efficiencies. The process of the present invention provides a more efficient method to make 1,2,3,4-tetrhaydroisoquinolines that can use a micro flow device.